Chronic fatigue syndrome (CFS) is an illness characterized by long-term fatigue, impaired memory or concentration, sore throat, tender lymph nodes, muscle pain, multi-joint pain, new headaches, unrefreshing sleep, and exercise intolerance. While the cause(s) of chronic fatigue syndrome has not been established definitively, a number of outbreaks implicate an infectious etiology. A variety of pathogens have been reported in individual CFS patients or found more frequently in CFS patients than controls, including various types of viruses. The immune systems of CFS patients exhibit both chronic activation and dysfunction. Recently, a new human retrovirus named XMRV (Xenotropic Murine Leukemia Virus-Related Virus) has been detected in a large proportion of CFS patients tested, but in only 4% of healthy subjects. We plan to learn more about the association of XMRV and other pathogens with CFS by examining an outbreak cohort not previously screened for the presence of XMRV. Other viruses, microbes, and parasites that may be associated with XMRV will also be detected with the use of a panmicrobial DNA microarray. We will determine whether the presence of XMRV and/or other pathogens is related to the current state of health of individuals who became ill during a 1985 outbreak in rural New York. Assuming that most members of the New York cohort are infected with XMRV, we will amplify and sequence XMRV envelope genes derived from blood cells of 40 individuals who became ill as children in 1985. We will also sequence envelope genes from 80 subjects in the Nevada cohort known to exhibit a high degree of XMRV infection. We will examine phylogenetic relationships between the Nevada and New York XMRV variants and will observe whether any amino acid substitutions correlate with the current state of health of the subjects. We will also study the possible association of XMRV and XMRV protein expression in the phenomenon of exercise intolerance. We will examine XMRV-infected CFS patients before and after an exacerbation of symptoms caused by serial exercise testing. We will determine whether increases in inflammatory cytokines, a growth factor, and nitric oxide, or blood cell changes are correlated with the extent of reduced physical ability that can be measured during a second exercise test taken after induction of postexertional malaise. All of these experiments will be designed to assess whether particular XMRV sequences and expression levels play a role in the symptoms experienced by CFS patients and to detect possible underlying mechanisms of the disability that impairs their physical activity. PUBLIC HEALTH RELEVANCE: Chronic fatigue syndrome, an illness that disables many Americans, has recently been associated with the presence of a new human retrovirus. We will investigate whether this retrovirus is both necessary and sufficient for the development of the illness, or whether additional pathogens are involved. We will determine whether the level of health and exercise intolerance in chronic fatigue syndrome is related to particular virus variants, expression of viral proteins, and/or dysfunction of the immune system.